Retinoblastoma (RB), an ocular tumor of childhood, consists of multipotent embryonic cells that have the potential to differentiate into neuronal or glial-like components. MHC class II antigens (HLA-DR, DQ, DP) are integral glycoproteins that are critical in immune regulation. The identification of these determinants on a variety of primitive stem cell types and tumor cells arrested at selected phases of their cell cycle has suggested that these molecules play a role in cellular differentiation. Recently, we demonstrated the presence of the class II molecules on RB cells. In addition, the modulation of HLA-DR by IFN gamma as well as the preferential expression of this determinant over HLA-DQ is described. Double-labeling experiments revealed that HLA-DR antigen is shared concomitantly with cells of glial and neuronal character. Based on these initial studies, additional investigations are in progress. One approach focuses on the correlation of class II antigen expression with cellular differentiation. A second examines the prognostic significance of these molecules on retinoblastoma cells and the possible relationship these proteins may have to the modulation and management of this tumor. Finally, a third study will examine the role of IFN-gamma as a differentiating agent of this tumor.